Rimantadine 207

71.Yen HL, Herlocher LM, Hoffmann E, et al. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother 2005; 49: 4075-84. Abstract: http://amedeo.com/lit.php?id=16189083

72.Yen HL, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis 2005; 192: 665-72. Abstract: http://amedeo.com/lit.php?id=16028136

Rimantadine

Introduction

Rimantadine is an M2 ion channel inhibitor which specifically inhibits the replication of influenza A viruses by interfering with the uncoating process of the virus. M2 inhibitors block the ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991). The influenza virus enters its host cell by re- ceptor-mediated endocytosis. Thereafter, acidification of the endocytotic vesicles is required for the dissociation of the M1 protein from the ribonucleoprotein complexes. Only then are the ribonucleoprotein particles imported into the nucleus via the nuclear pores. The hydrogen ions needed for acidification pass through the M2 channel. Rimantadine blocks the channel (Bui 1996).

The drug is effective against all influenza A subtypes that have previously caused disease in humans (H1N1, H2N2 and H3N2), but not against influenza B virus, because the M2 protein is unique to influenza A viruses. Rimantadine is not active against the avian flu subtype H5N1 strains that have recently caused disease in humans (Li 2004).

For both the prevention and treatment of influenza A, rimantadine has a comparable efficacy to amantadine but a lower potential for causing adverse effects (Stephenson 2001, Jefferson 2004).

The development of neutralising antibodies to influenza strains seems not to be affected by rimantadine. However, the presence of IgA in nasal secretions was significantly diminished in one study (Clover 1991).

A recently published study revealed an alarming increase in the incidence of aman- tadine-resistant and rimantadine-resistant H3N2 influenza A viruses over the past decade. In a recently published study, which assessed more than 7,000 influenza A viruses obtained worldwide from 1994 to 2005, drug resistance against amantadine and rimantadine increased from 0.4 % to 12.3 % (Bright 2005). Viruses collected in 2004 from South Korea, Taiwan, Hong Kong, and China show drug-resistance frequencies of 15 %, 23 %, 70 %, and 74 %, respectively. Some authors have suggested that the use of amantadine and rimantadine should be discouraged (Jefferson 2006). Recently, 109 out of 120 (91 %) of influenza A H3N2 viruses isolated from patients in the US contained an amino acid change at position 31 of the M2 protein, which confers resistance to amantadine and rimantadine. On the basis of these results, the Centre for Disease Control recommended that neither amantadine nor rimantadine be used for the treatment or prophylaxis of influenza A in the United States for the remainder of the 2005–06 influenza season (CDC 2006).

In most countries, rimantadine is not available.

208 Drug Profiles

Structure

Chemically, rimantadine hydrochloride is alpha-methyltricyclo-[3.3.1.1/3.7]decane- 1-methanamine hydrochloride, with a molecular weight of 215.77 and the following structural formula:

Pharmacokinetics

In healthy adults, peak plasma concentrations are reached 6 hours after oral administration. The single dose elimination half-life is about 30 hours in both adults (Hayden 1985) and children (Anderson 1987). Following oral administration, rimantadine is extensively metabolised in the liver and less than 25 % of the dose is excreted unchanged in the urine. In elderly people, the elimination is prolonged, with average AUC values and peak concentrations being 20 to 30 % higher than in healthy adults.

In chronic liver disease, rimantadine pharmacokinetics are not appreciably altered (Wills 1987); however, in patients with severe hepatic insufficiency, the AUC and the elimination half-life time are increased.

Renal insufficiency results in increased plasma concentrations of rimantadine metabolites. Haemodialysis does not remove rimantadine. Rimantadine dosage may therefore need to be reduced in patients with end-stage renal disease. Supplemental doses on dialysis days are not required (Capparelli 1988).

Toxicity

Gastrointestinal symptoms are the most frequent adverse events associated with rimantadine. Other side effects noted during clinical trials (all < 3 %) included nausea, vomiting, anorexia, and dry mouth, as well as CNS symptoms (insomnia, dizziness, nervousness). However, a study on the safety and efficacy of prophylactic long-term use in nursing homes showed no statistically significant differences in the frequencies of gastrointestinal or central nervous system symptoms between treatment and placebo groups (Monto 1995).

Less frequent adverse events (0.3 to 1 %) were diarrhoea, dyspepsia, impairment of concentration, ataxia, somnolence, agitation, depression, rash, tinnitus, and dyspnoea.